It is known that intracellular second messengers such as cAMP and cGMP are decomposed and inactivated by phosphodiesterase (“PDE”). Inhibition of PDE results in increase of intracellular cAMP and cGMP level. It is known that PDE can be classified into several isozymes each being different in terms of substrate (cAMP, cGMP) specificity, distribution in the body, and the like, and that, among isozymes, the type 4 PDE (“PDE4”) decomposes cAMP specifically.
There also have been known that inhibition of PDE4 activity can block the release of inflammatory mediator (J. Med. Cell. Cardiol. 21 (Suppl. II), S61 (1989), PDE4 inhibitor restrains the production of TNFαthat is a cytokine released from mononuclear phagocytes in response to immunostimulation, and is useful in treatment of various inflammatory diseases and the like (WO98/14432, WO98/09961, U.S. Pat. No. 6,011,060, WO98/02440, WO97/23457 and WO97/22585).
Theophylline, a representative PDE inhibitor, has hitherto been used in treatment of asthma. However, the PDE inhibitory activity of theophylline is non-specific, and it shows cardiotonic and central activity in addition to the bronchial smooth muscle relaxation activity. Thus, one must pay careful attention to this drug in view of such side effects. Accordingly, it has been desired to develop a new medical agent which can selectively inhibit PDE4 among PDE isozymes, which largely exists especially in bronchial smooth muscle and inflammatory cells. Such an agent is expected to be a promising medicine for prophylaxis and treatment of asthma or inflammatory diseases.
On the other hand, a certain compounds of pyrazinoisoquinoline type, specifically 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline shows central nervous system depressant and hypotensive effects. Indian J. Chem., vol. 13, 230-237 (1975).
As a naphthalene-type compound having PDE4 inhibitory activity, U.S. Pat. No. 6,005,106 discloses a compound wherein a nitrogen atom is directly attached to the pyridine ring at position 1 on the naphthalene moiety, but never discloses a compound wherein a carbon atom is directly attached to the pyridine ring at position 1 on the naphthalene moiety.